Biochemical and morphological assessments of bleomycin pulmonary toxicity in rats

Tom, Wai-Ming; Montgomery, Mark R.

doi:10.1016/0041-008x(80)90382-8

Cited by 26 publications

(4 citation statements)

References 21 publications

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“…In agreement with previous reports [4,23,28], a significant suppression of body weight gain was observed in the 4.5 and 6.0 mg/kg groups. However, there were no deaths on the day of dosing or during the 3-week observation period.…”

Section: Discussionsupporting

confidence: 81%

“…Therefore, in some cases, intratracheal administration of bleomycin under anesthesia induces death by respiratory failure (suffocation) during the dosing. Although intraperitoneal administration has been used [16,28] to avoid the disadvantages of the intratracheal administration, this method needs a longer duration for induction of pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 99%

“…This would be able to ensure a widespread distribution of the drug in the lung and to avoid the effects of anesthesia during drug administration. Since earlier studies conducted in rodents have mainly focused on the morphologic and/or biochemical aspects [5,11,14,28,31], we attempted to examine parameters of the blood gas and hematology in addition to body weight, organ weight, and histopathology.…”

Section: Introductionmentioning

confidence: 99%

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Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

et al. 2004

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Abstract:In order to ensure a widespread distribution in the lung and to avoid the effect of anesthesia, bleomycin at a total dose of 4.5 or 6.0 mg/kg was administered in four divided doses (0.5 ml/kg/time) at intervals of 2 h to male rats via a catheter (tracheotomy tube) without anesthesia. In comparison to vehicle (saline) controls, bleomycin-treated rats showed a significant suppression of body weight gain that was observed transiently at 4.5 mg/kg and continuously (throughout the 3-week observation period) at 6.0 mg/kg. Histopathologically, interstitial pneumonitis, thickening of alveolar walls, thickening of pulmonary arterial walls, foamy cells in alveoli, and hemorrhage were observed in both 4.5 and 6 mg/kg groups, and also emphysema in the 6 mg/kg group. Both groups exhibited a significant decrease in the partial pressure of arterial oxygen (PaO 2 ) and a significant increase in alveolar-arterial oxygen tension difference (AaDO 2 ), and a significant increase in erythrocyte count was observed in the 6 mg/kg group. Furthermore, both treated groups showed a significant increase in the ratio of the right ventricular weight versus left ventricle plus septum weights. The significant increase in erythrocyte count might have been caused by diffusion disturbance and ventilation-perfusion imbalance due to the pulmonary damage. These findings suggest that the present experimental method will be useful for clarification of the pulmonary damage induced by bleomycin in rats. Key words: bleomycin, catheter, diffusion disturbance, erythrocyte count, ventilationperfusion imbalance the precise mechanisms involved in the induction of this disease have not been clarified completely. In rodents, a single intratracheal administration under anesthesia is frequently used for preparing an animal model [7,10,23,26,32], but the extent and severity of pulmonary damage caused by bleomycin varies considerably depending on the attainability of the drug solution [16]. Furthermore, anesthesia itself causes respiratory and

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

et al. 2004

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“…We chose to administer bleomycin intratracheally because previous studies (Gong et al ., 2005 ; Zhou et al ., 2007) showed that a single dose was sufficient to produce marked histological and biochemical changes in most rodents within 1~4 weeks. In contrast, if test materials such as bleomycin were given IP, IV, or SC, it was necessary to use a relatively high dose over several weeks or to use implanted osmotic mini-pumps over the entire duration of the study (Tom and Montgomery, 1980 ; Briggs et al ., 1985 ; Harrison and Lazo, 1987 ; Brown et al ., 1988) . In present study, we used 3 consecutive levels of bleomycin to evaluate doseresponse effects.…”

Section: Discussionmentioning

confidence: 99%

Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

Kim¹,

Lee²,

Yang³

et al. 2010

Toxicological Research

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Many studies have reported that bleomycin, anti-cancer drug, induces pulmonary fibrosis as a side effect. However, few investigations have focused on the dose-response effects of bleomycin on pulmonary fibrosis. Therefore, in the present study, we investigated the effects of different doses of bleomycin in male mice. ICR mice were given 3 consecutive doses of bleomycin: 1, 2, or 4 mg/kg in bleomycin-treated (BT) groups and saline only in vehicle control (VC) groups. The animals were sacrificed at 7 and 24 days postinstillation. The severity of pulmonary fibrosis was evaluated according to inflammatory cell count and lactate dehydrogenase (LDH) activity in the broncho alveolar lavage fluid (BALF) , and lung tissues were histologically evaluated after hematoxylin and eosin (H&E) , and Masson’s trichrome staining. BT groups exhibited changed cellular profiles in BAL fluid compared to the VC group, which had an increased number of total cells, neutrophils, and lymphocytes and a modest increase in the number of macrophages at 7 days post-bleomycin instillation. Moreover, BT groups showed a dose-dependent increase in LDH levels and inflammatory cell counts. However, at 24 days after treatment, collagen deposition, interstitial thickening, and granulomatous lesions were observed in the alveolar spaces in addition to a decrease in inflammatory cells. These results indicate that pulmonary fibrosis induced by 4 mg/kg bleomycin was more severe than that induced by 1 or 2 mg/kg. These data will be utilized in experimental animal models and as basic data to evaluate therapeutic candidates through non-invasive monitoring using the pulmonary fibrosis mouse model established in this study.

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Effects of bleomycin on ¹⁴C‐proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices

Giri

Younker

Schiedt

1985

J of Applied Toxicology

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The uptake of 14C-proline by lung slices and its incorporation into trichloroacetic-acid (TCA)-insoluble proteins and hydroxylation in collagenous proteins were studied. They were found to be linearly increased with the incubation time for as long as 8 h. The effects of different concentrations of bleomycin on these parameters were subsequently investigated. Bleomycin at 10(-3) M significantly reduced the uptake of 14C-proline to 75% of the control value. The incorporation of 14C-proline into TCA-insoluble proteins was reduced to 84%, 78% and 75% of the control at 2.5 X 10(-4) M, 5 X 10(-4) M and 10(-3) M concentrations of bleomycin, respectively. Bleomycin failed to alter the proline pool size of the lung slices at any of these concentrations. In addition, bleomycin also inhibited the hydroxylation of 14C-proline into collagen to 72% and 69% of the control at 5 X 10(-4) M and 10(-3) M, respectively. These findings show that bleomycin-induced increases in collagen synthesis in vivo is probably secondary to inflammatory reactions of the lung and bleomycin per se has little effect on increased collagen synthesis responsible for lung fibrosis.

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Biochemical and morphological assessments of bleomycin pulmonary toxicity in rats

Cited by 26 publications

References 21 publications

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

Effects of bleomycin on ¹⁴C‐proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices

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Biochemical and morphological assessments of bleomycin pulmonary toxicity in rats

Cited by 26 publications

References 21 publications

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Intratracheal Administration of Bleomycin via a Catheter in Unanesthetized Rats.

Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

Effects of bleomycin on 14C‐proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices

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Effects of bleomycin on ¹⁴C‐proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices